Sanders-Brown Center on Aging, University of Kentucky, 101 Sanders-Brown Bldg., 800 S. Limestone Street, Lexington, KY, 40536, USA.
Department of Neuroscience, University of Kentucky, Lexington, KY, USA.
J Neuroinflammation. 2020 Sep 17;17(1):274. doi: 10.1186/s12974-020-01938-7.
Elevated blood homocysteine levels, termed hyperhomocysteinemia (HHcy), is a prevalent risk factor for Alzheimer's disease (AD) in elderly populations. While dietary supplementation of B-vitamins is a generally effective method to lower homocysteine levels, there is little if any benefit to cognition. In the context of amyloid pathology, dietary-induced HHcy is known to enhance amyloid deposition and certain inflammatory responses. Little is known, however, about whether there is a more specific effect on microglia resulting from combined amyloid and HHcy pathologies.
The present study used a knock-in mouse model of amyloidosis, aged to 12 months, given 8 weeks of B-vitamin deficiency-induced HHcy to better understand how microglia are affected in this comorbidity context.
We found that HHcy-inducing diet increased amyloid plaque burden, altered the neuroinflammatory milieu, and upregulated the expression of multiple damage-associated and "homeostatic" microglial genes.
Taken together, these data indicate complex effects of comorbid pathologies on microglial function that are not driven solely by increased amyloid burden. Given the highly dynamic nature of microglia, their central role in AD pathology, and the frequent occurrence of various comorbidities in AD patients, it is increasingly important to understand how microglia respond to mixed pathological processes.
血液同型半胱氨酸水平升高，即高同型半胱氨酸血症（HHcy），是老年人群中阿尔茨海默病（AD）的一个普遍危险因素。虽然补充 B 族维生素通常是降低同型半胱氨酸水平的有效方法，但对认知几乎没有任何益处。在淀粉样蛋白病理的背景下，已知饮食诱导的 HHcy 会增强淀粉样蛋白沉积和某些炎症反应。然而，对于由于淀粉样蛋白和 HHcy 合并病理而导致的小胶质细胞是否存在更具体的影响，知之甚少。
本研究使用淀粉样蛋白病的基因敲入小鼠模型，年龄为 12 个月，给予 8 周的 B 族维生素缺乏诱导 HHcy，以更好地了解小胶质细胞在这种合并症背景下是如何受到影响的。
我们发现 HHcy 诱导饮食增加了淀粉样斑块负担，改变了神经炎症环境，并上调了多种损伤相关和“稳态”小胶质细胞基因的表达。
综上所述，这些数据表明合并病理对小胶质细胞功能的复杂影响不仅仅是由增加的淀粉样蛋白负担驱动的。鉴于小胶质细胞的高度动态性质、它们在 AD 病理中的核心作用以及 AD 患者中各种合并症的频繁发生，了解小胶质细胞如何对混合病理过程做出反应变得越来越重要。
